Prolactin drives estrogen receptor-α-dependent ductal expansion and synergizes with transforming growth factor-α to induce mammary tumors in males
Prolactin drives estrogen receptor-α-dependent ductal expansion and synergizes with transforming growth factor-α to induce mammary tumors in males
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DOI：
10.2353/ajpath.2008.070597
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发表时间：
2008-01-01
影响因子：
6
通讯作者：
Schuler, Linda A.
中科院分区：
文献类型：
--
作者：
Arendt, Lisa M.;Schuler, Linda A.
男性乳腺癌很罕见，一直是有限研究的焦点。虽然病因尚不清楚，但增加循环催乳素（PRL）以及雌激素的条件会增加肿瘤发生的风险。我们使用乳腺选择性、雌激素不敏感的启动子neu相关脂质运载蛋白（NRL）来模拟转基因小鼠暴露于升高的PRL来驱动PRL表达。雄性NRL-PRL小鼠未发生乳腺肿瘤。然而，在合作的良好特征的癌基因转化生长因子-α（TGF-α），催乳素诱导乳腺肿瘤在100%的雄性双转基因小鼠。与人类男性的疾病相似，这些肿瘤表达不同水平的雌激素受体-a（ER-a）和雄激素受体。然而，睾丸激素对癌变没有反应，因为去势并没有改变肿瘤发展或肿瘤ER-α表达的潜伏期。有趣的是，NRL-TGF-α/PRL和NRL-PRL雄性都表现出增加的导管发育，这发生在青春期，类似于雌性小鼠。在用ICI 182，780处理的NRL-PRL雄性中，这种生长减少，表明PRL增强ER介导的生长。用PRL处理MCF-7衍生的细胞增加了ER-α在涉及未配体ER-α活性的残基处的磷酸化。总之，这些研究表明，PRL扩大了对肿瘤发生敏感的细胞库，然后通过PRL和TGF-α相互作用促进肿瘤发生。ER-α的激活是PRL可能导致乳腺癌的一种机制，并指出了男性患者的其他治疗策略。
Male breast cancer is rare and has been the focus of limited research. Although the etiology is unclear, conditions increasing circulating prolactin (PRL), as well as estrogen, increase the risk of tumorigenesis. We modeled exposure to elevated PRL in transgenic mice, using the mammary-selective, estrogen-insensitive promoter neu-related lipocalin (NRL), to drive PRL expression. Male NRL-PRL mice did not develop mammary tumors. However, in cooperation with the well-characterized oncogene transforming growth factor-alpha (TGF-alpha), PRL induced mammary tumors in 100% of male bitransgenic mice. Similar to disease in human males, these tumors expressed variable levels of estrogen receptor-a (ER-a) and androgen receptors. However, carcinogenesis was not responsive to testicular steroids because castration did not alter latency to tumor development or tumor ER-a expression. Interestingly, both NRL-TGF-alpha/PRL and NRL-PRL males demonstrated increased ductal development, which occurred during puberty, similar to female mice. This outgrowth was diminished in NRL-PRL males treated with ICI 182,780, suggesting that PRL enhances ER-mediated growth. Treatment of MCF-7-derived cells with PRL increased phosphorylation of ER-a at residues implicated in unliganded ER-a activity. Together, these studies suggest that PRL expands the pool of cells susceptible to tumorigenesis, which is then facilitated by PRL and TGF-a cross talk. Activation of ER-a is one mechanism by which PRL may contribute to breast cancer and points to other therapeutic strategies for male patients.